Eisen's research[2][15][16] focuses on the origin of novelty, how new processes and functions originate in living things. To study this, he focuses on sequencing and analyzing genomes of organisms, especially microbes and using phylogenomic analysis.

Eisen and his work is routinely discussed in the scientific and popular press. Examples include a New York Times article on the Genomic Encyclopedia of Bacteria and Archaea in 2009[21] and extensive coverage of work on searching for a "fourth domain" of life.[22][23] In addition, Eisen's blogging and microblogging work is frequently written about including for example.[24][25][26] His brother Michael Eisen is also a biologist.

^ abGegger, Laura (December 24, 2012). "These Were a Few of Their Favorite Things". The New York Times. Jonathan Eisen: 44, evolutionary biologist, University of California, Davis, and academic editor in chief of PLoS Biology